This invention relates to 4-substituted piperidine xcex23-adrenergic receptor agonists useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
The subdivision of xcex2 adrenergic receptors (xcex2-AR) into xcex21- and xcex22-AR has led to the development of xcex21- and xcex22-antagonists and/or agonists which have been useful for the treatment of cardiovascular disease and asthma. The recent discovery of xe2x80x9catypicalxe2x80x9d receptors, later called xcex23-AR, has led to the development of xcex23-AR agnoists which may be potentially useful as antiobesity and antidiabetic agents. For recent reviews on xcex23-AR agnoists, see: 1. A. D. Strosberg, Annu. Rev. Pharmacol. Toxicol. 1997, 37, 421; 2. A. E. Weber, Ann. Rep. Med. Chem. 1998, 33, 193; 3. C. P. Kordik and A. B. Reitz, J. Med. Chem. 1999, 42, 181; 4. C. Weyer, J. F. Gautier and E. Danforth, Diabetes and Metabolism, 1999, 25, 11.
One essential requirement for the development of xcex23-AR agonist is selectivity. Any substantial xcex21- or xcex22-agonism would likely cause increased heart rate or muscle tremor, respectively, both are unacceptable side effects in a drug. Early developments in the xcex23-agonist field are described in European patent 427480, U.S. Pat. Nos. 4,396,627, 4,478,849, 4,999,377, 5,153,210. Although the early developments purport to claim compounds with greater xcex23-AR selectivity over the xcex21- and xcex22-AR, however, clinical trials in humans with those early developed xcex23-agonists have, so far, not been successful.
More recently, potent and selective human xcex23 agonists have been described in several patents and published applications: WO 98/32753, WO 97/46556, WO 97/37646, WO 97/15549, WO 97/25311, WO 96/16938, WO 95/29159, European Patents 659737, 801060, 714883, 764640, 827746, and U.S. Pat. Nos. 5,561,142, 5,705,515, 5,436,257, and 5,578,620. These compounds were evaluated in Chinese hamster ovary (CHO) cells test procedures which predicts the effects that can be expected in humans. These assays utilize cloned human xcex23 receptors, expressed in CHO cells (see refs. Granneman et al., Mol Pharmacol., 1992, 42, 964; Emorine et al., Science, 1989, 245, 1118; Liggett Mol. Pharmacol., 1992, 42, 634).
xcex23-Adrenergic agonists also are useful in controlling the frequent urge of urination. It has been known that relaxation of the bladder detrusor is under beta adrenergic control (Li JH, Yasay GD and Kau ST. Beta-adrenoceptor subtypes in the detrusor of guinea-pig urinary bladder. Pharmacology 1992; 44: 13-18). Recently, a number of laboratories have provided experimental evidence in a number of animal species including human (Yamazaki Y, Takeda H, Akahane M, Igawa Y, et al. Species differences in the distribution of the beta-adrenoceptor subtypes in bladder smooth muscle. Br. J. Pharmacol. 1998; 124: 593-599) that activation of the xcex23 receptor subtype by norepinephrine is responsible for relaxation of the urinary bladder. Urge urinary incontinence is characterized by abnormal spontaneous bladder contractions that can be unrelated to bladder urine volume. Urge urinary incontinence is often referred to hyperactive or unstable bladder. Several etiologies exist and fall into two major categories, myogenic and neurogenic. The myogenic bladder is usually associated with detrusor hypertrophy secondary to bladder outlet obstruction, or with chronic urinary tract infection. Neurogenic bladders are associated with an uninhibited micturition reflex. An upper motor neuron disease is usually the underlying cause. In either case, the disease is characterized my abnormal spontaneous contractions that result in an abnormal sense of urinary urgency and involuntary urine loss. At present, the most common therapy for hyperactive bladder includes the use of antimuscarinic agents to block the action of the excitatory neurotransmitter acetylcholine. While effective in neurogenic bladders, their utility in myogenic bladders is questionable. In addition, due to severe dry mouth side-effects associated with antimuscarinic therapy, the patient compliance with these agents is only approximately 30%.
In the bladder, xcex23 adrenergic receptor agonists activate adenylyl cyclase and generate cAMP through the G-protein coupled xcex23 receptor. The resulting phosphorylation of phospholamban/calcium ATPase enhances uptake of calcium into the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits bladder smooth muscle contractility.
It is suggested therefore, that activation of the xcex23 adrenergic receptor in the urinary bladder will inhibit abnormal spontaneous bladder contractions and be useful for the treatment of bladder hyperactivity. Note, that unlike the antimuscarinics, xcex23 adrenergic receptor agonists would be expected to be active against both neurogenic and myogenic etiologies.
Despite all these recent developments there is still no single therapy available for the treatment of type II diabetes (NIDDM), obesity, atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, frequent urination and related diseases. A potent and selective xcex23 adrenergic receptor agonist is therefore highly desirable for the potential treatment of such disease states.
This invention provides compounds of Formula I having the structure 
wherein, 
(a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, substituted with (R1)m;
(b) a phenyl ring substituted with (R1)m;
(c) a naphthyl ring substituted with (R1)m; or
(d) a phenyl fused heterocycle selected from the group consisting of 
U is xe2x80x94OCH2xe2x80x94 or a bond;
V is O or a bond;
W is O, S(O)a; NR2, or NCOR2;
X is SO2, CO, xe2x80x94(CH2)bxe2x80x94, a bond, or Ar;
Y is xe2x80x94NR3R4, Het, Ar, alkyl of 1-8 carbon atoms, or xe2x80x94O(CH2)dR5;
R1 is alkyl of 1-8 carbon atoms, alkenyl of 2-7 carbon atoms, xe2x80x94OR6, halogen, cyano, trifluoromethyl, xe2x80x94CO2R6, xe2x80x94CONR6R7, xe2x80x94NHCOR6, or NHSO2R8;
R2 is hydrogen, alkyl of 1-8 carbon atoms, or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
R3 and R4 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl group, xe2x80x94(CH2)gR9, xe2x80x94(CH2)hCOR9, xe2x80x94(CH2)jCR10R11(CH2)jR9, or xe2x80x94(CH2)kCONR12R13; or R3 and R4 may be taken together together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R14;
R5 is hydrogen; alkyl of 1-8 carbon atoms optionally substituted by 1-3 substituents selected from hydroxy, halogen, and aryl; cycloalkyl of 1-8 carbon atoms; Ar or Het;
R6, R7, and R8 are each, independently, hydrogen, or alkyl of 1-8 carbon atoms, or aryl of 6-10 carbon atoms;
R9 is hydrogen; alkyl optionally substituted with 1-3 substitutents selected from hydroxy, halogen, and aryl; cycloalkyl of 3-8 carbon atoms; Ar, or Het;
R10 and R11 are each, independently, hydrogen, alkyl, or aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R10 and R11 are taken together to form a spiro fused cycloalkyl ring of 3-8 carbon atoms;
R12 and R13 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R12 and R13 are taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R14;
R14 is CO2R15 or aryl optionally substituted with a 1-3 substituents selected from xe2x80x94OR15 and cycloalkyloxy of 3-8 carbon atoms;
R15 is alkyl of 1-8 carbon atoms or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms optionally mono-, di-, or tri-substituted with R16;
Het is (a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, S, and N which may be optionally mono- or di-substituted with R16; or (b) a heterocyclic ring system optionally mono- or di-substituted by R16 containing a 5-6 membered heterocyclic ring fused to one or two carbocyclic or heterocyclic rings such that the heterocyclic ring system contains 1-4 heteroatoms selected from O, S, and N;
R16 is aryl, halogen, alkyl of 1-8 carbon atoms, xe2x80x94OR17, cycloalkyl of 3-8 carbon atoms, trifluoromethyl, cyano, xe2x80x94CO2R17, xe2x80x94CONR17R18, xe2x80x94SO2NR17R18, xe2x80x94NR19CONR17R18, xe2x80x94NR17R18, xe2x80x94NR17COR18, xe2x80x94NO2, xe2x80x94O(CH2)pCO2R17, xe2x80x94OCONR17R18, xe2x80x94O(CH2)qOR17, or a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from O, S, and N;
R17, R18, and R19 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl moiety, or aryl optionally mono-, di-, or tri-substituted with halogen, cyano, nitro, hydroxy, alkyl of 1-8 carbon atoms, or alkoxy of 1-8 carbon atoms; or when R17 and R18 are contained on a common nitrogen, R17 and R18 may be taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S;
a=0-2;
b=1-6;
d=0-3;
g=0-6;
h=0-6;
j=0-6;
k=0-6;
m=0-2;
p=1-6;
q=1-6;
or a pharmaceutically acceptable salt thereof, which are selective agonists at human xcex23 adrenergic receptors and are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable aids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, such as alkali metal salts (for example, sodium, lithium, or potassium) alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group, when a compound of this invention contains an acidic moiety.
The compounds of the instant invention all contain at least one asymmetric center. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, are included within the scope of the instant invention. Any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials of know configuration. In the case of the asymmetric center represented by the asterisk in formula Ia, it has been found that the compound in which the hydroxy substituent is above the plane of the structure, is preferred over the compound in which the hydroxy substituent is below the plane of the structure. 
Alkyl and alkenyl include both straight chain as well as branched moieties. Halogen means bromine, chlorine, fluorine, and iodine. Aryl includes monocyclic or bicyclic aromatic carbocyclic groups such as phenyl and naphthyl. Benzyl is the preferred arylalkyl moiety.
As used herein, a heterocyclic ring is a ring contining 1-4 heteroatoms selected from N, O, and S, indicates a heterocycle which may be saturated, unstaurated, or partially unsaturated. Further definition may be derived from the substituents of the heterocycle. The monocyclic, bicyclic, or tricyclic heterocycles described above are unsubstituted, or mono- or di-substituted on any available carbon or nitrogen atoms. The heterocyclic ring may be attached within structural Formula I by any carbon atom or heteroatom. It is understood that the heterocyclic ring does not contain heteroatoms in arrangements which would make them inherently unstable. For example, the term heterocyclic ring does not include ring systems containing Oxe2x80x94O bonds in the ring backbone. Preferred heterocycles include pyridyl, pyrimidinyl, pyrrolyl, piperidyl, pyrrolidinyl, indazolyl, morpholinyl, thienyl, furyl, imidazolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzothiadiazolyl, benzodioxolyl, benzodioxanyl, benzoxazinyl, benzofuryl, dihydrobenzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzooxadiaxolyl, benzofurazanyl, furopyridine, and thienopyridine.
Preferred compounds of Formula I are those in which 
(a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, substituted with (R1)m;
(b) a phenyl ring substituted with (R1)m;
(c) a phenyl fused heterocycle selected from the group consisting of 
U is xe2x80x94OCH2xe2x80x94 or a bond;
V is O or a bond;
W is O, S(O)a; or NR2;
X is SO2, CO, xe2x80x94(CH2)bxe2x80x94, a bond, or Ar;
Y is xe2x80x94NR3R4, Het, Ar, alkyl of 1-8 carbon atoms, or xe2x80x94O(CH2)dR5;
R1 is alkyl of 1-8 carbon atoms, alkenyl of 2-7 carbon atoms, aryl of 6-10 carbon atoms, xe2x80x94OR6, cycloalkyl of 3-8 carbon atoms, halogen, cyano, trifluoromethyl, xe2x80x94CO2R6, xe2x80x94CONR6R7, xe2x80x94NHCOR6, NHSO2R6, xe2x80x94NR6CONR7R8, xe2x80x94NR6R7, alkenyl of 2-7 carbon atoms, S(O)aR6, NO2, xe2x80x94O(CH2)eCO2R6, xe2x80x94OCONR6R7, xe2x80x94O(CH2)fOR6, or a 5-6 membered heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, and N;
R2 is hydrogen, alkyl of 1-8 carbon atoms, or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
R3 and R4 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl group, xe2x80x94(CH2)gR9, xe2x80x94(CH2)hCOR9, xe2x80x94(CH2)jCR10R11(CH2)jR9, or xe2x80x94(CH2)kCONR12R13; or R3 and R4 may be taken together together with the, nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R14;
R5 is hydrogen; alkyl of 1-8 carbon atoms optionally substituted by 1-3 substituents selected from hydroxy, halogen, and aryl; cycloalkyl of 1-8 carbon atoms; Ar or Het;
R6, R7, and R8 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, aryl of 6-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
R9 is hydrogen; alkyl optionally substituted with 1-3 substitutents selected from hydroxy, halogen, and aryl; cycloalkyl of 3-8 carbon atoms; Ar, or Het;
R10 and R11 are each, independently, hydrogen, alkyl, or aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R10 and R11 are taken together to form a spiro fused cycloalkyl ring of 3-8 carbon atoms;
R12 and R13 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R12 and R13 are taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R14;
R14 is CO2R15 or aryl optionally substituted with a 1-3 substituents selected from xe2x80x94OR15 and cycloalkyloxy of 3-8 carbon atoms;
R15 is alkyl of 1-8 carbon atoms or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms optionally mono-, di-, or tri-substituted with R16;
Het is (a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, S, and N which may be optionally mono- or di-substituted with R16; or (b) a heterocyclic ring system optionally mono- or di-substituted by R16 containing a 5-6 membered heterocyclic ring fused to one or two carbocyclic or heterocyclic rings such that the heterocyclic ring system contains 1-4 heteroatoms selected from O, S, and N;
R16 is aryl, halogen, alkyl of 1-8 carbon atoms, xe2x80x94OR17, cycloalkyl of 3-8 carbon atoms, trifluoromethyl, cyano, xe2x80x94CO2R17, xe2x80x94CONR17R18, xe2x80x94SO2NR17R18, xe2x80x94NR17OR18, xe2x80x94NR19CONR17R18, xe2x80x94NR17R18, xe2x80x94NR17COR18, xe2x80x94S(O)nR17, xe2x80x94NO2, xe2x80x94O(CH2)pCO2R17, xe2x80x94OCONR17R18, xe2x80x94O(CH2)qOR17, or a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from O, S, and N;
R17, R18, and R19 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl moiety, or aryl optionally mono-, di-, or tri-substituted with halogen, cyano, nitro, hydroxy, alkyl of 1-8 carbon atoms, or alkoxy of 1-8 carbon atoms; or when R17 and R18 are contained on a common nitrogen, R17 and R18 may be taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S;
a=0-2;
b=1-6;
d=0-3;
e=1-6;
f=1-6;
g=0-6;
h=0-6;
j=0-6;
k=0-6;
m=0-2;
n=0-2;
p=1-6;
q=1-6;
or a pharmaceutically acceptable salt thereof.
Specifically preferred compounds of this invention are:
a) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
b) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid cyclohexylamide;
c) 4-(4-{2-[(2S)-3-(4-Fluoro-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
d) 4-(4-{2-[(2S)-3-(2-Allyl-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
e) 4-(4-{2-[(2S)-3-(6-Amino-pyridin-3-yloxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
f) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid [2-(3-methoxy-phenyl)-ethyl]-amide;
g) 4-(4-{2-[2-(3-Carbamoyl-4-hydroxy-phenyl)-2-hydroxy-ethylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
h) 4-[Acetyl-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenyl)-amino]-piperidine-1-carboxylic acid octylamide;
i) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid methylamide;
j) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid ethylamide;
k) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid isopropyl-amide;
l) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-cyclopentyl-propyl)-amide;
m) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (2,2,2-trifluoro-ethyl)-amide;
n) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid diethylamide;
o) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide;
p) 4-(4-{2-[(2S)-3-(2-Chloro-4-hydroxy-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
q) [4-(3-Cyclopentyloxy-4-methoxy-phenyl)-piperidin-1-yl]-[4-[4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-methanone;
r) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid amide;
s) 4-[4-(2-{(2S)-3-[4-(3-Ethyl-ureido)-phenoxy]-2-hydroxy-propylamino}-ethyl)-phenylamino]-piperidine-1-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide;
t) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,4-dichloro-benzylamide;
u) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 3,4-dichloro-benzylamide;
v) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-methanesulfonylamino-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
w) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxyphenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-thiophen-2-yl-propyl)-amide;
x) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 3,5-difluoro-benzylamide;
y) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,3-dimethoxy-benzylamide;
z) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2-fluoro-benzylamide;
aa) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 3-fluoro-benzylamide;
bb) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-oxo-3-p-tolyl-propyl)-amide;
cc) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-p-tolyl-propyl)-amide;
dd) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide;
ee) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (2,2-diphenyl-ethyl)-amide;
ff) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,6-difluoro-benzylamide;
gg) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2-trifluoromethyl-benzylamide;
hh) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 4-pyrazol-1-yl-2-trifluoromethyl-benzylamide;
ii) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-methyl-butyl)-amide;
jj) 4-(4-{2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
kk) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,5-difluoro-benzylamide;
ll) 5-[(S)-3-[[2-[4-[[1-[[[(2,5-Difluorophenyl)methyl]amino]carbonyl]-4-piperidinyl]amino]phenyl]ethyl]amino]-2-hydroxypropoxy]-2-hydroxybenzoic acid;
mm) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethoxy}-phenylamino)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
nn) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylsulfanyl)-piperidine-1-carboxylic acid phenylamide;
oo) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylsulfanyl)-piperidine-1-carboxylic acid hexylamide;
pp) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylsulfanyl)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
qq) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylsulfanyl)-piperidine-1-carboxylic acid (1-phenyl-cyclopentylmethyl)-amide;
rr) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-benzenesulfonyl)-piperidine-1-carboxylic acid hexylamide;
ss) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-benzenesulfonyl)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
tt) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-benzenesulfonyl)-piperidine-1-carboxylic acid (1-phenyl-cyclopentylmethyl)-amide;
uu) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-benzenesulfonyl)-piperidine-1-carboxylic acid octylamide;
vv) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-3-methyl-phenoxy)-propylamino]-ethyl}-benzenesulfonyl)-piperidine-1-carboxylic acid octylamide;
ww) 4-(4-{2-[(2S)-3-(Benzo[1,3]dioxol-5-yloxy)-2-hydroxy-propylamino]-ethyl}-benzenesulfonyl)-piperidine-1-carboxylic acid octylamide;
xx) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-3-methanesulfonylamino-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,5-difluoro-benzylamide;
yy) 1-[4-(4-{2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-piperidine-4-carboxylic acid ethyl ester;
zz) 1-[4-(4-{2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-piperidine-4-carboxylic acid;
aaa) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
bbb) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenoxy)-piperidine-1-carboxylic acid octylamide;
ccc) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (8-fluoro-octyl)-amide;
ddd) 4-(4-{2-[(2S)2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenoxy)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
eee) 4-(4-{2-[2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid [4-(3,4-dimethoxy-phenyl)-butyl]-amide;
fff) (4-{[4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-amino}-phenoxy)-acetic acid;
ggg) 4-(4-{2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
hhh) 4-(4-{2-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
iii) 1-[4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-piperidine-4-carboxylic acid ethyl ester;
jjj) 1-[4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-piperidine-4-carboxylic acid;
kkk) 4-(4-{2-[(2S)-3-(3-Acetylamino-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
lll) 4-(4-{2-[(2S)-2-Hydroxy-3-(5-hydroxy-3,4-dihydro-2H-naphthalen-1-ylideneaminooxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
mmm) 4-(4-{2-[(2S)-3-(3-Fluoro-4-hydroxy-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
nnn) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-3-methanesulfonylamino-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
ooo) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 4-(3-hexyl-ureido)-benzylamide;
ppp) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-cyclohexyl-propyl)-amide;
qqq) 4-(4-{2-[(2S)-2-Hydroxy-3-(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-5-yloxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylicacid octylamide;
rrr) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid cyclopentylmethyl-amide;
sss) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid {2-[2-methoxy-4-(3-phenoxy-propoxy)-phenyl]-ethyl}-amide;
ttt) 4-(4-{2-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-ethoxy}-phenylamino)-piperidine-1-carboxylic acid octylamide;
uuu) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethoxy}-phenylamino)-piperidine-1-carboxylic acid octylamide;
vvv) Dimethyl-carbamic acid 4-(2-{[4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-amino}-ethyl)-phenyl ester;
www) 4-(4-{2-[(2S)-2-Hydroxy-3-(3-methanesulfonylamino-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
xxx) 4-(4-{2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,5-difluoro-benzylamide;
yyy) 1-[[4-[[4-[2-[[(2R)-2-Hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]ethyl]phenyl]amino]-1-piperidinyl]carbonyl]-L-proline, methyl ester;
zzz) 1-[[4-[[4-[2-[[(2R)-2-Hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]ethyl]phenyl]amino]-1-piperidinyl]carbonyl]-3-piperidine carboxylic acid, ethyl ester;
aaaa) 4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]ethyl}phenylamino)-piperidine-1-carboxylic acid 3-methoxy-benzylamide;
bbbb) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,4-difluoro-benzylamide;
cccc) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid [2-(4-fluoro-phenylcarbamoyl)-ethyl]-amide;
dddd) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid {2-[(4-chloro-phenyl)-methyl-carbamoyl]-ethyl}-amide;
eeee) 4-(4-{2-[2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2-fluoro-4-hydroxy-benzylamide;
ffff) Dimethyl-carbamic acid 3-fluoro-4-({[4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-amino}-methyl)-phenyl ester;
gggg) 4-(4-{2-[(2S)-2-Hydroxy-3-(3-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
hhhh) [3-Fluoro-4-[[[[4-[[4-[2-[[(S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]phenyl]amino]-1-piperidinyl]carbonyl]amino]methyl]phenoxy]acetic acid;
iiii) 4-(4-{2-[(2S)-2-Hydroxy-3-(3-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2-fluoro-4-hydroxy-benzylamide;
jjjj) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid [2-(3-fluoro-phenyl)-ethyl]-amide;
kkkk) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (2-diethylcarbamoyl-ethyl)-amide;
llll) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-morpholin-4-yl-3-oxo-propyl)-amide;
mmmm) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(1H-indol-2-yl)-methanone;
nnnn) 4-[4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid octylamide;
oooo) 1-Hexyl-3-{4-[4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-phenyl}-urea;
pppp) [4-(4-{2-[2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(5-methoxy-1H-indol-2-yl)-methanone;
qqqq) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(7-nitro-1H-indol-2-yl)-methanone;
rrrr) (5-Bromo-1H-indol-2-yl)-[4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-methanone;
ssss) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(3-methoxy-benzo[b]thiophen-2-yl)-methanone;
tttt) N-{3-[(2S)-2-Hydroxy-3-(2-{4-[1-(3-methoxy-benzo[b]thiophene-2-carbonyl)-piperidin-4-ylamino]-phenyl}-ethylamino)-propoxy]-phenyl}-acetamide;
uuuu) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(1H-indol-3-yl)-methanone;
vvvv) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(3-methyl-thiophen-2-yl)-methanone;
wwww) 4-[(2S)-2-Hydroxy-3-(2-{4-[1-(3-methyl-thiophene-2-carbonyl)-piperidin-4-ylamino]-phenyl}-ethylamino)-propoxy]-1,3-dihydro-benzoimidazol-2-one;
xxxx) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(1H-indazol-3-yl)-methanone;
yyyy) 1-[4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-hexan-1-one;
zzzz) [(2S)-1-(4-Fluoro-benzenesulfonyl)-pyrrolidin-2-yl]-[4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-methanone;
aaaaa) 4-[4-(4-{2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-benzoic acid;
bbbbb) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylsulfanyl)-piperidin-1-yl]-(3-methyl-thiophen-2-yl)-methanone;
ccccc) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-benzenesulfonyl)-piperidin-1-yl]-(2-methyl-thiophen-3-yl)-methanone;
ddddd) 1-Hexyl-3-{4-[4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-sulfonyl]-phenyl}-urea;
eeeee) 1-{4-[4-(4-{2-[(2S)-3-(4-Fluoro-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-piperidine-1-sulfonyl]-phenyl}-3-hexyl-urea;
fffff) 1-{4-[4-(4-{2-[3-(2-allyl-phenoxy)-2-hydroxy-propylamino]ethyl}-phenylamino)-piperidine-1-sulfonyl]-phenyl}-3-hexyl-urea;
ggggg) 4-[(2S)-2-Hydroxy-3-(2-{4-[1-(octane-1-sulfonyl)-piperidin-4-ylamino]-phenyl}-ethylamino)-propoxy]-phenol;
hhhhh) 4-[(2S)-2-Hydroxy-3-(2-{4-[1-(toluene-4-sulfonyl)-piperidin-4-ylamino]-phenyl}-ethylamino)-propoxy]-phenol;
iiiii) 4-[(2S)-2-Hydroxy-3-(2-{4-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-ylamino]-phenyl}-ethylamino)-propoxy]-phenol;
jjjjj) N-{4-[4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-sulfonyl]-phenyl}-acetamide;
kkkkk) N-(5-{[4-(4-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]ethyl}anilino)piperidin-1-yl]sulfonyl}-4-methyl-1,3-thiazol-2-yl)acetamide;
lllll) N-(2-Hydroxy-5-{(1R)-1-hydroxy-2-[2-(4-{1-[4-(3-octyl-ureido)-benzenesulfonyl]-piperidin-4-ylamino}-phenyl)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;
mmmmm) 4-[(2S)-2-Hydroxy-3-(2-{4-[1-(4-phenyl-thiazol-2-yl)-piperidin-4-ylamino]-phenyl}-ethylamino)-propoxy]-phenol;
nnnnn) (R)-N-{2-Hydroxy-5-[1-hydroxy-2-(2-{4-[1-(4-phenyl-thiazol-2-yl)-piperidin-4-ylamino]-phenyl}-ethylamino)-ethyl]-phenyl}-methanesulfonamide;
ooooo) N-(2-Hydroxy-5-{(1R)-1-hydroxy-2-[2-(4-{1-[4-(piperidine-1-sulfonyl)-phenyl]-piperidin-4-ylamino}-phenyl)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;
ppppp) 4-[4-(4-{2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl}-phenylamino)-piperidin-1-yl]-benzoic acid ethyl ester;
qqqqq) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 4-fluoro-benzyl ester;
rrrrr) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,5-difluoro-benzyl ester
or a pharmaceutically acceptable salt thereof.
The compounds of this invention were be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These schemes show the preparation of representative compounds of this invention. 
When U represents xe2x80x94OCH2xe2x80x94 compounds of the present invention can be prepared from epoxide intermediate such as those of Formula (II) and amine intermediates such as those of Formula (IV). The preparation of these intermediates is described in the following schemes. 
When U is a bond compounds of the present invention can be prepared from epoxide intermediates such as those of Formula (IV) and amine intermediates of Formula (III). Alternatively, an intermediate of Formula (V) may be reacted with amine intermediates of Formula (III). In a further method of preparation intermediates of Formula (VI) may be reacted with aldehydes having the Formula (VII). The preparation of these intermediates is described in the following schemes. 
Compounds of Formula (II) can be conveniently prepared by a variety of methods familiar to those skilled in the art. One common route is illustrated in Scheme 1. Alcohol (VIII) is treated with base such as sodium hydride or potassium t-butoxide in a polar solvent such as anhydrous dimethylformamide. The resulting anion is alkylated with a suitable epoxide derivative, wherein, xe2x80x9cLxe2x80x9d is a leaving group such as a sulfonate ester or a halide, for 0.5 to 24 hours at a temperature of 20-100xc2x0 C. to provide epoxide (II). The reacting epoxide derivative is conveniently the commercially available, enantiomerically pure (2S) or (2R)-glycidyl 3-nitrobenzene sulfonate, or (2R) or (2S)-glycidyl 4-toluenesulfonate, thus both (S) and (R) enantiomers of epoxide (III) are available. J. M. Klunder et al., J. Org. Chem., 1989, 54, 1295.
Alternatively, compounds of Formula (II) can be conveniently prepared from alcohol (VIII) under Mitsunobu conditions reaction (O. Mitsunobu, Bull. Chem. Soc. Jpn., 1967, 60, 2380,) reacting the commercially available, enantiomerically pure (2S) or (2R)-glycidol, with triphenyl phosphine and a dialkyl azodicarboxylate in an anhydrous solvent such as tetrahydrofuran at 20-35xc2x0 C. for 12-36 hours, suitable alkyl groups are ethyl, isopropyl etc., Scheme 2.
Many of the alcohols are commercially available or readily prepared by methods described in the literature and known to those skilled in the art. R1 substitutions on the alcohol (VIII) may need to be protected during the reaction with the epoxide derivatives and subsequent procedures. A description of such protecting groups may be found iN Protective Groups in Organic Synthesis, 2nd Ed., T. W. Greene and P. G. M. Wut, John Wiley and Sons, New York, 1991.
A useful method for protecting the preferred alcohol wherein (R1)m is 4-hydroxyphenyl is as its tert-butyldiphenylsilyl (TBDPS) derivative shown in Scheme 3. Commercially available 4-(benzyloxy)phenol is treated with a silylating agent such as tert-butyldiphenylsilyl chloride in the presence of an organic base such as imidazole in an inert anhydrous solvent such as dichloromethane. The resulting compound (IX) is then treated under transfer hydrogenation conditions using Pd/C and cyclohexene in ethanol at reflux for 12-24 hours to prepare the alcohol (X). 
Epoxides of Formula (IV) are known in the literature or may be conveniently prepared by a variety of methods familiar to those skilled in the art. One common route is shown in Scheme 4.
Methyl ketone (XI) may be converted to the corresponding haloketone using a variety of reagents known to those skilled in the art and summarised in Larock, Comprehensive Organic Transformations, VCH, New York, 1989, 369-372. For the synthesis wherein X=Br, bromine or dibromobarbituric acid may be used. The reduction of the haloketone is conveniently performed with a reducing agent such as sodium borohydride. The resulting alcohol when treated with a base such as sodium hydroxide or potassium carbonate in a suitable solvent such as 2-butanone or acetone yields the epoxide of Formula (IV).
The enantiomercially enriched (R) or (S)-epoxide (IV) are readily available by asymmetric reduction of haloketones (XII) using chiral reducing agents in place of sodium borohydride. Such chiral reducing agents include (xe2x88x92) or (+)-DIP-Cl, (R) or (S)-Alpine borane or (R) or (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,21]oxazaborole-borane ((R) or (S)xe2x80x94OAB.BH3). Alternatively the haloketones (XII) may be treated with borane in the presence of a chiral auxiliary agent such as described by E. J. Corey et al., J. Org. Chem., 1991, 56, 442,
Compound (V) can be conveniently prepared by substantially following the literature procedure reported by E. J. Corey and J. O. Link, J. Org. Chem., 1991, 56, 422, and patent WO 9737646 wherein haloketones such as (XII) are transformed into compounds (V) by sequential halogenation, asymmetric reduction followed by transformation to the iodide and finally protection of the alcohol as a silyl ether. 
Compound (XIV) can be conveniently prepared by utilizing the alcohol (XV) (following asymmetric reduction) and displacement of the halogen with a metal azide such as sodium or lithium azide in an a aprotic solvent such as dimethylformamide in the presence of sodium iodide at 20-40xc2x0 C. for 5-10 days. Reduction of the azide group to generate amines of the Formula (XIV) is conveniently performed by catalytic reduction on a Parr apparatus with a suitable catalyst such as palladium on carbon. If (R1)m contains a protecting group removed by hydrogen such as benzyl then this group will also be removed under the reaction conditions. 
Many of the methyl ketones are commercially available or readily prepared by methods described in the literature and known to those skilled in the art. R1 substitutions on the methyl ketones may need to be protected during the reaction with the epoxide derivatives and subsequent procedures. A description of such protecting groups may be found in Protective Groups in Organic Synthesis, 2nd Ed., T. W. Greene and P. G. M. Wut, John Wiley and Sons, New York, 1991.
Compounds of Formula (III) can be conveniently prepared by a variety of methods familiar to those skilled in the art.
A convenient route for their preparation when W is nitrogen is illustrated in Scheme 7. Compound (XVI) is selectively protected as a suitable carbamate derivative. Di-tert-butyl dicarbonate reacts preferrentially in an inert solvent such dichloromethane at ambient temperature to provide the tert-butyl carbamate protected primary amine (XVII)
Compounds of Formula (XVIII) may be conveniently formed under reductive amination conditions. Such conditions and reagents are well known in the art. They are typically performed by mixing the amine and carbonyl compound in a solvent and adding a reducing agent. Solvents typically include lower alcohols, dichloromethane, DMF and the like. A wide variety of reducing agents can be utilized, most commonly utilized are sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. The temperature of the reaction is typically room temperature to the reflux of the solvent. 
This reaction is most conveniently performed substantially as described by J. W. Coe et al Tet. Letts., 1996, 37, 6045. Wherein compounds of Formula (XVII) are pre-stirred at ambient temperature with the ketone in an inert solvent such as dichloromethane or dichloroethane in the presence of a drying agent such as anhydrous sodium sulfate and an acid such as acetic acid. Typically the reductant employed is sodium triacetoxyborohydride which is added in excess after 45-50 minutes.
When Xxe2x80x94Y together represent a benzyl protecting group then the commercially available 1-benzyl-4-piperidinone provides a most convenient route to compounds of the general Formula (XIX) shown in Scheme 8.
The protecting benzyl group of compounds of Formula (XIX) can be removed under a number of condition described in Protective Groups in Organic Synthesis, 2nd Ed., T. W. Greene and P. G. M. Wut, John Wiley and Sons, New York, 1991. One such method is palladium catalysed transfer hydrogenation with cyclohexene in boiling ethanol essentially as described by S. Ram, Synthesis, 1988, 91.
This strategy, in addition to that in Scheme 7, thus provides an alternative method to provide compounds of Formula (III) since they can be conveniently prepared from compounds of Formula (XX) by a variety of methods familiar to those skilled in the art and described below. Where W of Formula (III) represents an alkylated or acylated nitrogen atom of reaction of the nitrogen with for example, in the case of acylation, acetic anhydride in pyridine prior to the removal of the benzyl group and reaction of the liberated secondary amine. 
When V is a bond commercially available 4-(2-aminoethyl)aniline can be conveniently used in the sequence described above.
When V is xe2x80x94OCH2xe2x80x94 then methods described in the literature can be conveniently employed to prepare as shown in Scheme 9.
The sodium salt of 4-nitrophenol is alkylated with 1-p-tosylchloroethane, conveniently in refluxing 2-butanone with a base such as potassium carbonate to give the corresponding tosyl derivative as described by N. Ackerley et al., J. Med. Chem., 1995, 38(10), 1608-28. The tosyl group is converted to the amine by treatment with a metal azide such as sodium or lithium azide in an a aprotic solvent such as dimethylformamide followed by reduction with, for example, triphenylphosine in aqueous tetrahydrofuran as described by H. Staudinger, Helv. Chim. Acta, 1919, 2, 635. Protection of the resulting amine, conveniently as the t-butyl carbamate with di-tert-butyl dicarbonate is followed by reduction of the nitro group by, for example, palladium catalyzed hydrogenation to provide the amine (XXII). Aniline (XXII) is thus able to undergo essentially similar transformations as amine (XVII) to provide compounds of Formula (III).
Aldehydes of Formula (VII) may be prepared by a variety of procedures known in the art. The following is an example for the preparation of aldehydes of general Formula (VII). 
When V is a bond commercially available 4-nitrobenzeneethanol provides a suitable convenient starting material. Mild neutral oxidation using reagents such as Dess-Martin periodinane (P. B. Martin, J. Am. Chem. Soc., 1978, 100, 300) in an inert solvent such as dichloromethane is advantageous. The resulting aldehyde can be protected as an acetal or ketal in situ. A number of such groups are described in Protective Groups in Organic Synthesis, 2nd Ed., T. W. Greene and P. G. M. Wut, John Wiley and Sons, New York, 1991. A convenient procedure is to protect the aldehyde as the di-methyl acetal by reaction of the aldehyde with anhydrous trimethylorthoformate and an organic acid such as p-toluenesulfonic acid. Reduction of the nitro group can be carried out in a variety of ways, conveniently reduction with palladium on carbon in refluxing ethanol with an excess of ammonium formate provides the desired aniline. Aniline (XXIII) Is thus able to undergo essentially similar transformations as amine (XVII) to provide compounds of Formula (III).
When W is oxygen or sulfur compounds of Formula (III) can be conveniently prepared by a variety of methods familiar to those skilled in the art. One such route (W=O and V=bond) is illustrated in Scheme 11.
Commercially available tyramine can be selectively protected as a suitable carbamate derivative with, for example, di-tert-butyl dicarbonate or carbobenzyloxy chloride. 4-Piperidinol can be preferentially reacted at the nitrogen or protected at the oxygen with a suitable protecting group such as tert-butyldiphenyl silyl. Once groups Xxe2x80x94Y have been added (as described below) then removal of the protecting group with for example tetrabutylammonium fluoride can be performed if needed or the alcohol reacted directly. Methods to convert the alcohol group of the N-substituted 4-piperidinol to a suitable leaving group shown in (XXIV) are known to those skilled in the art. One particularly mild and convenient procedure is shown in Scheme 12. Treatment with carbon tetrabromide and tripheny phosphine in an inert solvent such as dichloromethane as described by J. Hooz et. al., Can. J. Chem., 1968, 46, 96 provides bromide (XXVI). 
An alternative procedure is the Mitsunobu reaction (O. Mitsunobu, Bull. Chem. Soc. Jpn., 1967, 60, 2380). Treatment of (XXVI) with triphenyl phosphine and a dialkyl azodicarboxylate in an anhydrous solvent such as tetrahydrofuran at 20-35xc2x0 C. for 12-36 hours, suitable alkyl groups are ethyl, isopropyl etc. occurs readily and provides a preferred mild method for the in situ reaction (XXVI) to provide compounds Formula (XXV).
When W is sulfur compounds of Formula (III) can be conveniently prepared by a variety of methods familiar to those skilled in the art. One such route is illustrated in Scheme 13.
The aniline group of (XVII) wherein R=BOC is diazotized with sodium nitrite in cold hydrochloric acid and then coupled to potassium ethylxanthate (K. K. Jensen and V. H. Mikkelsen, Arch. Pharm. Chemi., 1941, 48, 665). The xanthate (XXVIII) is then treated under standard reducing conditions with a alkali metal hydride such as sodium borohydride or lithium aluminum hydride (D. A. Jaeger and J. Wang, J. Org. Chem., 1993, 58, 6745) and reacted with (XXIV) to provide (XXIX). The preparation of suitable intermediates (XXIV) has been described above. Oxidation of sulfur in (XXIX) provides access to compounds of the Formula (XXX) where a=1 or 2. Standard oxidation conditions for this transformation may be found in M. Hudlicky, Oxidation in Organic Chemistry, American Chemical Society, Washington D.C., 1990. Most conveniently 3-chloroperoxybenzoic acid in an inert solvent such as dichloromethane when reacted with an equimolar amount of (XXIX) provides (XXX) wherein a=2 and with (XXIX) in a halfmolar amount provides (XXX) wherein a=1.
When Xxe2x80x94Y in Formula (XXXII) (Scheme 14) represents a urea group compounds of this nature may be prepared under a variety of conditions. Many isocyanates are commercially available and can be conveniently reacted directly with (XXXI) in an inert solvent such as tetrahydrofuran to yield the desired ureas. Alternatively, amines can be reacted in the presence of triphosgene and a hindered organic base such as di-isopropylethylamine as described by P. Mayer and R. M. Randad, J. Org. Chem., 1994, 59, 1937. Furthermore, acids can be reacted in a one-pot procedure with diphenylphosphoryl azide and compound (XXIV) to yield the desired ureas as described by K. Ninomiya et al Tetrahedron, 1974, 30, 2151.
When Xxe2x80x94Y in Formula (XXXII) (Scheme 14) represents a sulfonamide group compounds of this general Formula can be prepared directly with sulfonyl halides, many of which are commercially available. Typical reaction conditions include treating compound (XXXI) with the sulfonyl halide in an anhydrous solvent such as dichloromethane or chloroform for 0.5 to 24 hours at temperatures of xe2x88x9220 to 50xc2x0 C. to provide sulfonamides of Formula (XXXII). Sulfonyl halides can also be prepared by a number of methods familiar to those skilled in the art. One such method for aromatic and heteroaromatic compounds is the treatment of the aromatic or heteroaromatic compound directly with Vilsmier""s reagent or chlorosulfonyl chloride.
When Xxe2x80x94Y in Formula (XXXII) (Scheme 14) represents an amide bond compounds of this general Formula can be conveniently prepared by reaction of the corresponding acid suitably activated. Many such activating groups may be employed. Such methodology is described in M. Bodansky and A. Bodansky, The Practice of Peptide Synthesis, Springer-Verlag, 1984, 87-150. Many acids are commercially available and can be readily prepared by those skilled in the art. Two most convenient reagents are the water-soluble carbodiimide 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride typically in an inert solvent such as dichloromethane and the BOP-reagent: benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophophate typically in an aprotic solvent such as N,N-dimethylformamide with an tertiary organic base such as triethylamine.
When Xxe2x80x94Y in Formula (XXXII) (Scheme 14) represents a carbamate group compounds of this general Formula can be conveniently prepared by a variety of conditions. A typical representative is illustrated by the reaction of a corresponding alcohol suitably activated. One convenient procedure is described by N. Choy Organic Preparations and Procedures International, 1996, 28, 173. A cooled combined solution of an alcohol and 4-nitrochloroformate in a suitable anhydrous solvent such as tetrahydrofuran together with a hindered organic base such as triethylamine or an inorganic base such as potassium carbonate is prepared and subsequently treated with the amine (XXXI) to provide compounds wherein (XXXII) is a carbamate group. Many of the alcohols are commercially available or readily prepared by methods described in the literature and known to those skilled in the art.
Alternatively, suitably protected amines (XXI) can be prepared conveniently by following Scheme 15. Wherein the secondary amine is first reacted before reductive amination occurs. Ordinarily suitable protection step of the ketone group will need to be utilized. Commercially available 1,4-dioxa-8-azaspiro[4.5]decane provides a convenient intermediate. 
Commercially available 1,4-dioxa-8-azaspiro[4.5]decane can be reacted to elaborate Xxe2x80x94Y prior to removal of the cyclic ketal for which a variety of methods are available as described in Protective Groups in Organic Synthesis, 2nd Ed., T. W. Greene and P. G. M. Wut, John Wiley and Sons, New York, 1991. One convenient procedure is the use of formic acid for 0-2 hours at 45-65xc2x0 C. Reductive amination of the ketone with the aniline (XVI) or (XXII) as described above furnishes compounds of Formula (XVIII). Alternatively reductive amination with (XXIII) may be utilized. However, this methodology is particularly useful when the presence of the aniline nitrogen in compound of Formula (XX) could lead to unwanted side reactions. Representative examples are shown below.
When X in Formula (XXXII) represents a direct bond this methodology is a favored method of preparation. A variety of conditions can be utilized to provide such compounds. One such procedure which is provided as an example (Scheme 16) involves reaction of 1,4-dioxa-8-azaspiro[4.5]decane (XXXIII) with an aromatic or heteroaromatic halide in the presence of an acid scavenger such as potassium carbonate in an anhydrous aprotic solvent such as N,N-dimethylformamide. The reaction is typically performed at temperatures 90-120xc2x0 C. for 12 to 48 hours. 
Further transformations may be carried out, such as hydrolysis of ester groups typically with an aqueous base such as aqueous lithium hydroxide in tetrahydrofuran or sodium hydroxide in aqueous methanol, the protecting ketal can be directly removed and reductive amination performed to furnish compounds of Formula (XXXII).
In another method aromatic groups may be introduced by construction of the aromatic group rather than halide displacement. This method is most suitable to heteroaromatic groups and one such example is given in Scheme 17.
Thiourea (XXXV) was prepared using substantially the method described by M. A. Poss Tet. Letts., 1992, 33, 5933. Ring formation can be brought about with a a-halo ketone in an anhydrous aprotic solvent such as N.N-dimethylformamide at 50-90xc2x0 C. for 0.5-24 hours. Further transformations may be carried out or the ketal can be directly removed and reductive amination performed with (XVI) to furnish compounds of Formula (XVIII).
Final deprotection of the elaborated protected amines can be conducted using a number of acidic conditions.
When the protecting group is the tert-butyl carbamate one such convenient acid is formic acid. On dissolving the protected tert-butylcarbamate-amines in formic acid with warming removal of the protecting group is smoothly performed.
Reaction with epoxides:
The correspondingly obtained formate salts may be either be utilized with the epoxides of Formula (II) or (IV) to furnish the amino alcohols by reaction in an alcoholic solvent with heat in the presence of a hindered organic base such triethylamine or N,N-diisopropylamine or may be treated with aqueous base to yield the amines free of salt. The desired amino alcohols can thus be obtained by reaction with epoxides (II) or (IV). In those cases where the amine or amine salt is reacted with iodide (XIII) then the procedure described by E. J. Corey and J. O. Link, J. Org. Chem., 1991, 56, 422, namely heated in an anhydrous solvent such as tetrahydrofuran, furnished the desired amino alcohols.
When the protecting group is the dimethyl acetal then a number of methods are described in Protective Groups in Organic Synthesis, 2nd Ed., T. W. Greene and P. G. M. Wut, John Wiley and Sons, New York, 1991, for the removal of the dimethyl acetal to furnish compounds of Formula (VII). However, one such method was preferred. Thus essentially as described by G. A. Olah et. al., J. Org. Chem., 1983, 48, 3667, protected acetals were treated with trichloromethylsilane and sodium iodide in acetonitrile to furnish compounds of Formula (VII).
Aldehydes of Formula (VII) can be conveniently reacted with amines of Formula (III) under reductive amination conditions. Such conditions and reagents are well known in the art. They are typically performed by mixing the amine and carbonyl compound in a solvent and adding a reducing agent. Solvents typically include lower alcohols, dichloromethane, DMF and the like. A wide variety of reducing agents can be utilized, most commonly utilized are sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. The temperature of the reaction is typically room temperature to the reflux of the solvent.
The compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. The compounds of this invention are therefore, particularly useful in the treatment or inhibition of type II diabetes. The compounds of this invention are also useful in modulating glucose levels in disorders such as type I diabetes.
The ability of compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was confirmed with representative compounds of this invention in the following standard pharmacological test procedures, which measured the binding selectivity to the xcex21, xcex22, and xcex23 adrenergic receptors. Binding to the receptors was measured in Chinese Hamster ovary (CHO) cells that were transfected with adrenergic receptors. The following briefly summarizes the procedures used and results obtained.
Transfection of CHO cells with xcex21 and xcex22 adrenergic receptors: CHO cells were transfected with human xcex21- or xcex22-adrenergic receptors as described in Tate, K. M., Eur. J. Biochem., 196:357-361(1991).
Cloning of Human xcex23-AR Genomic DNA: cDNA was constructed by ligating four polymerase chain reaction (PCR) products using the following primers: an ATG-Narl fragment, sense primer 5xe2x80x2-CTTCCCTACCGCCCCACGCGCGATC3xe2x80x2 and anti-sense primer 5xe2x80x2CTGGCGCCCAACGGCCAGTGGCCAGTC3xe2x80x2; a Narl-Accl fragment, 5xe2x80x2TTGGCGCTGATGGCCACTGGCCGTTTG3xe2x80x2 as sense and 5xe2x80x2GCGCGTAGACGAAGAGCATCACGAG3xe2x80x2 as anti-sense primer; an Accli-Styl fragment, sense primer 5xe2x80x2CTCGTGATGCTCTTCGTCTCACGCGC3xe2x80x2 and anti-sense primer 5xe2x80x2GTGAAGGTGCCCATGATGAGACCCAAGG3xe2x80x2 and a Styl-TAG fragment, with sense primer 5xe2x80x2CCCTGTGCACCTTGGGTCTCATCATGG3xe2x80x2 and anti-sense primer 5xe2x80x2CCTCTGCCCCGGTTACCTACCC3xe2x80x2. The corresponding primer sequences are described in Mantzoros, C. S., et. al., Diabetes 45: 909-914 (1996). The four fragments are ligated into a pUC 18 plasmid (Gibco-BRL) and sequenced. Full length xcex23 AR clones (402 amino acids) containing the last 6 amino acids of hxcex23xe2x80x94AR are prepared with the xcex23-xcex2ARpcDNA3 from ATTC.
Binding Procedure: Clones expressing receptor levels of 70 to 110 fmoles/mg protein were used in the test procedures. CHO cells were grown in 24-well tissue culture plates in Dulbecco""s Modified Eagle Media with 10% fetal bovine serum, MEM non-essential amino acids, Penicillin-Streptompycin and Geneticin. On the day of test procedure, growth medium was replaced with preincubation media (Dulbecco""s Modified Eagle Media and incubated for 30 minutes at 37xc2x0 C. Preincubation medium was replaced with 0.2 ml treatment medium containing DMEM media containing 250 xcexcM IBMX (isobutyl-1-methylxantine) plus 1 mM ascorbic acid with test compound dissolved in DMSO. Test compounds were tested over a concentration range of 10xe2x88x929M to 10xe2x88x925M for xcex23 cells and 10xe2x88x928 to 10xe2x88x924M for xcex21 and xcex22 transfected cells. Isoproterenol (10xe2x88x925M) was used as an internal standard for comparison of activity. Cells were incubated at 37xc2x0 C. on a rocker for 30 min with the xcex23 cells and 15 min for xcex21 and xcex22 cells. Incubation was stopped with the addition of 0.2N HCl and neutralized with 2.5N NaOH. The plates, containing the cells and neutralized media, were stored at xe2x88x9220 degrees celsius until ready to test for cAMP using the SPA test kit (Amersham).
Data Analysis and Results: Data collected from the SPA test procedure were analyzed as per cent of the maximal isoproterenol response at 10xe2x88x925M. Activity curves were plotted using the SAS statistical and graphics software. EC50 values were generated for each compound and the maximal response (IA) developed for each compound is compared to the maximal response of isoproternol at 10xe2x88x925M from the following formula:
IA=% activity compound
% activity isoproterenol
Table I shows the xcex23-adronergic receptor EC50 and IA values for the representative compounds of this invention that were evaluated in this standard pharmacological test procedure. These results show that compounds of the present invention have activity at the xcex23-adrenergic receptor. The compounds of this inventon had weaker or no activity at xcex21 and/or xcex22-adrenergic receptor.
Based on the results obtained in these standard pharmacological test procedures, representative compounds of this invention have been shown to be selective xcex23 adrenergic receptor agonists and are therefore useful in treating metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes, and in modulating glucose levels in disorders such as type I diabetes. As used herein, the term modulating means maintaining glucose levels within clinically normal ranges.
As used in accordance with this invention, the term providing an effective amount means either directly administering such a compound of this invention, or administering a prodrug, derivative, or analog which will form an effective amount of the compound of this invention within the body.
It is understood that the effective dosage of the active compounds of this invention may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated. As used in accordance with invention, satisfactory results may be obtained when the compounds of this invention are administered to the individual in need at a daily dosage of from about 0.1 mg to about 1 mg per kilogram of body weight, preferably administered in divided doses two to six times per day, or in a sustained release form. For most large mammals, the total daily dosage is from about 3.5 mg to about 140 mg. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
Such doses may be administered in any manner useful in directing the active compounds herein to the recipient""s bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, intranasally, vaginally, and transdermally. For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s).
In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol.
The compounds of this invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository""s melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.
The compounds of the present invention also possess utility for increasing lean meat deposition and/or improving lean meat to fat ratio in edible animals, i.e. ungulate animals and poultry.
Animal feed compositions effective for increasing lean meat deposition and for improving lean meat to fat ratio in poultry, swine, sheep, goats, and cattle are generally prepared by mixing the compounds of the present invention with a sufficient amount of animal feed to provide from about 1 to 1000 ppm of the compound in the feed. Animal feed supplements can be prepared by admixing about 75% to 95% by weight of a compound of the present invention with about 5% to about 25% by weight of a suitable carrier or diluent. Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, sodium chloride, cornmeal, cane molasses, urea, bone meal, corncob meal and the like. The carrier promotes a uniform distribution of the active ingredients in the finished feed into which the supplement is blended. It thus performs an important function by ensuring proper distribution of the active ingredient throughout the feed. The supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.
The preferred medicated swine, cattle, sheep and goat feed generally contain from 0.01 to 400 grams of active ingredient per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed. The preferred poultry and domestic pet feed usually contain about 0.01 to 400 grams and preferably 10 to 400 grams of active ingredient per ton of feed.
For parenteral administration the compounds of the present invention may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean mean to fat ratio is sought. In general, parenteral administration involves injection of a sufficient amount of the compounds of the present invention to provide the animal with 0.001 to 100 mg/kg/day of body weight of the active ingredient. The preferred dosage for swine, cattle, sheep and goats is in the range of from 0.001 to 50 mg/kg/day of body weight of active ingredient; whereas, the preferred dose level for poultry and domestic pets is usually in the range of from 0.001 to 35 mg/kg/day of body weight.
Paste formulations can be prepared by dispersing the active compounds in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like. Pellets containing an effective amount of the compounds of the present invention can be prepared by admixing the compounds of the present invention with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process. It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the increase in lean meat deposition and improvement in lean meat to fat ratio desired. Moreover, it has been found that implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal""s body. For the poultry and swine raisers, using the method of the present invention yields leaner animals.
Additionally, the compounds of this invention are useful in increasing the lean mass to fat ratio in domestic pets, for the pet owner or veterinarian who wishes to increase leanness and trim unwanted fat from pet animals, the present invention provides the means by which this can be accomplished.
The following general procedures were used in preparing representative compounds of this invention, and are referred to as applicable.
A mixture of 1 molar equivalent of a hydroxyaryl compound, 1 molar equivalent of (S)-(+)-glycidyl 3-nitrobenzenesulfonate and 1.2 molar equivalent of potassium carbonate in approx. 0.25 molar 2-butanone was heated at reflux for 18 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel Merck-60.
An approx. 0.3 molar solution of a hydroxyaryl compound, R-(+)-glycidol and triphenylphosphine in anhydrous tetrahydrofuran was treated drop-wise with 1.1 molar equivalent of diethyl azodicarboxylate. After stirring the reaction mixture at ambient temperature overnight, the solvent was removed in vacuo and the residue purified by flash chromatography on silica gel Merck-60 eluting with the specified solvent.
Triphosgene (0.37 molar equivalent) was dissolved in anhydrous dichloromethane. To this solution, was added drop-wise, a mixture of the amine (1 molar equivalent) and N,N-diisopropylethylamine (1.1 molar equivalents) in dichloromethane over 1 hour at ambient temperature. After the addition, a second mixture containing an amine (1 molar equivalent) and anhydrous N,N-diisopropylethylamine (1.1 equivalent) in anhydrous dichloromethane was added in one portion. In those cases where solubility needed to be increased then anhydrous tetrahydrofuran was substituted for anhydrous dichloromethane either in part or in total. The reaction was stirred at ambient temperature for 1 hour. The solvent was removed in vacuo and the residue dissolved in a suitable organic solvent and washed with aqueous sodium bicarbonate solution, brine and water. The organic layer was dried over anhydrous sodium (or magnesium) sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography on silica gel Merck-60 eluting with the specified solvent.
An acid (1 molar equivalent) and anhydrous N,N-diisopropylethylamine (1.1 molar equivalents) were combined anhydrous toluene (approx. 0.1M solution). Diphenylphosphoryl azide (1.2 molar equivalents) was added and the reaction stirred at ambient temperature for 0.5 hour. The reaction was heated to 85xc2x0 C. for 1 hour prior to the addition of the amine (1 molar equivalent). The heat was removed, and the reaction allowed to cool, dichloromethane was added and the organic phases washed with 1N sodium hydroxide, 1N hydrochloric acid, 1N sodium hydroxide, water, brine, and dried with anhydrous sodium (or magnesium) sulfate. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel Merck-60 eluting with the specified solvent.
A mixture of 1 molar equivalent each of the amine and substituted isocyanate was stirred at ambient temperature in dichloromethane or tetrahydrofuran for 1 hour. The reaction mixture was diluted with dichloromethane and washed with 1N hydrochloric acid, water, and brine. The organic layer was dried over anhydrous sodium (or magnesium) sulfate, filtered, and the solvent removed in vacuo. The product was purified by flash chromatography on silica gel Merck-60 eluting with the specified solvent.
The tert-butylcarbamate protected amine was dissolved in formic acid (excess) and stirred at room temperature (heating to 60xc2x0 C. for 5-10 minutes may also be employed). The formic acid was evaporated under reduced pressure co-evaporating in vacuo with a mixture of chloroform/ethanol achieve a 1:1 formate salt.
The amine (either as the formate salt or as a free base) was dissolved in ethanol with anhydrous N,N-diisopropylethylamine (if the amine salt were employed theN 1.1-1.5 molar equivalents). The reaction mixture was heated at 60xc2x0 C. overnight. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel Merck-60 eluting with the specified solvent.
The diphenyl-tert-butylsilyl protected phenol was dissolved in anhydrous tetrahydofuran at ambient temperature and tert-butylammonium fluoride (generally 1 molar equivalent of a 1M tetrahydrofuran solution was sufficient) was added. The reaction was stirred at ambient temperature for 10-60 minutes. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel Merck-60 eluting with the specified solvent.
A solution of the secondary amine was prepared by dissolving the amine (1 molar equivalents) in acetic acid. Succinic anhydride (1 molar equivalent) was added. The suspension was stirred overnight at ambient temperature. The acetic acid was removed in vacuo and the resulting oil was taken up in ethyl acetate and washed with 0.1N hydrochloric acid and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the title acid. An analytical sample was obtained by crystallization from ethyl acetate.
To a solution of a molar equivalent of the alcohol and 2.1 molar equivalents of carbon tetrabromide in a mixture of dichloromethane and tetrahydrofuran (3 to 1 ratio) at 5xc2x0 C. was added 2.1 molar equivalents of triphenylphosphine, portion-wise. After addition, the ice/water bath was removed and the reaction was stirred overnight at ambient temperature. Diethyl ether was added and the reaction mixture filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel Merck-60 eluting with the specified solvent.
To a solution of a molar equivalent of S-(4-{2-[(tert-butoxycarbonyl)amino]-ethyl}phenyl) O-ethyl carbonodithioate in degassed dry ethanol was added 2.5 molar equivalents of sodium borohydride. This was warmed to 45xc2x0 C. for 1 hour. The reaction was cooled to room temperature and 1 molar equivalent of the bromide added, the reaction mixture-was warmed to 50xc2x0 C. and stirred for 3 hours. The cooled treated with dilute hydrochloric acid and the pH adjusted to 7.5. The mixture was concentrated in vacuo, taken up into dichloromethane, dried, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel Merck-60 (elutant: 1:2 ethyl acetate-hexane).
The tert-butylcarbamate protected amine was dissolved in dichloromethane/trifluoro-acetic acid/methanol (100/25/1 v/v ratio) and stirred for 4 hours at ambient temperature. The volatile components were evaporated in vacuo and the residue taken up into dichloromethane and washed with aqueous sodium bicarbonate. The organic phase was dried, filtered and evaporated in vacuo to provide the deprotected amine.
To a solution of a molar equivalent of the sulfide (tert-butyl carbamate protected amine) in dichloromethane at 0xc2x0 C. was added 2.2 molar equivalents of 3-chloroperoxybenzoic acid in dichloromethane. After 1 hour, the ice/water bath was removed and the reaction was stirred 1 hour more. Additional dichloromethane was added and the reaction mixture was washed with dilute aqueous sodium dithionite followed by aqueous sodium bicarbonate. The organic phase was dried, filtered and evaporated in vacuo. The residue was purified by filtration through silica gel Merck-60 eluting with dichloromethane-diethyl ether (1/1)
The following describes the preparation of intermediates useful in the preparation of the compounds of this invention.